U.S. patent application number 10/343014 was filed with the patent office on 2004-03-11 for modified hollow-fiber membrane.
Invention is credited to Imamura, Kazuo, Ishihara, Kazuhiko, Kamenosono, Koji, Miyazaki, Shinji, Nakabayashi, Nobuo, Suzuki, Ken.
Application Number | 20040045897 10/343014 |
Document ID | / |
Family ID | 18720898 |
Filed Date | 2004-03-11 |
United States Patent
Application |
20040045897 |
Kind Code |
A1 |
Nakabayashi, Nobuo ; et
al. |
March 11, 2004 |
Modified hollow-fiber membrane
Abstract
A modified hollow-fiber membrane which has improved surface
hydrophilicity without increasing the amount of components released
therefrom, is less apt to interact with living-body components,
does not adsorb proteins, and is less apt to deteriorate in
performance. The hollow-fiber membrane has a copolymer of
2-methacryloyloxyethylphosphorylcholine and other polymerizable
vinyl monomer held on a surface of the membrane, the copolymer
being present on the surface in a higher concentration than in
other parts of the membrane. The modified hollow-fiber membrane is
useful in medical applications such as hemodialysis and blood
filtration and in the medical industry, food industry etc.
Inventors: |
Nakabayashi, Nobuo; (Chiba,
JP) ; Ishihara, Kazuhiko; (Tokyo, JP) ;
Miyazaki, Shinji; (Nobeoka-shi, JP) ; Imamura,
Kazuo; (Fujisawa-shi, JP) ; Suzuki, Ken;
(Tsukuba-shi, JP) ; Kamenosono, Koji;
(Nishinomiya-shi, JP) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET 2ND FLOOR
ARLINGTON
VA
22202
|
Family ID: |
18720898 |
Appl. No.: |
10/343014 |
Filed: |
June 2, 2003 |
PCT Filed: |
July 27, 2001 |
PCT NO: |
PCT/JP01/06487 |
Current U.S.
Class: |
210/500.23 ;
210/500.24 |
Current CPC
Class: |
B01D 69/08 20130101;
B01D 71/28 20130101; B01D 67/0088 20130101; B01D 67/0013 20130101;
B01D 71/40 20130101; B01D 2323/12 20130101; B01D 69/02 20130101;
B01D 71/76 20130101; B01D 67/0016 20130101 |
Class at
Publication: |
210/500.23 ;
210/500.24 |
International
Class: |
B01D 069/08; B01D
071/40 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 27, 2000 |
JP |
2000-227448 |
Claims
1. A hollow fiber membrane made from a synthetic polymer which
holds a copolymer of 2-methacryloyloxyethyl phosphorylcholine and
other vinyl-polymerizable monomers on the surface thereof, wherein
said copolymer is presented in a higher concentration on inside
and/or outside surface of the membrane than the other parts of the
membrane.
2. The hollow fiber membrane according to claim 1, wherein the
synthetic polymer is selected from the group consisting of
polysulfone-based, polycarbonate-based, polyamide-based, polyvinyl
chloride-based, polyvinyl alcohol-based, polyallylate-based,
polyacrylonitrile-based, polyether-based, polyester-based,
polyurethane-based, and polyacrylate-based polymers and mixtures of
these polymers.
3. The hollow fiber membrane according to claim 1 or 2, wherein the
synthetic polymer is a mixture of polysulfone and/or polyether
sulfone and polyvinyl pyrrolidone.
4. The hollow fiber membrane according to claim 1, wherein the
synthetic polymer forming thick membrane parts in the hollow fiber
membrane is a synthetic polymer having a contact angle in the range
of 50.degree. to 100.degree..
5. The hollow fiber membrane according to any one of claims 1-4,
wherein the copolymer held on the surface of the membrane has a
monomer unit content of 2-methacryloyloxyethyl phosphorylcholine in
the range of 0.05 to 0.95.
6. The hollow fiber membrane according to any one of claims 1-5,
wherein the monomer unit concentration of 2-methacryloyloxyethyl
phosphorylcholine on the surface of the membrane is 5 wt % or
more.
7. The hollow fiber membrane according to any one of claims 1-6,
wherein the other vinyl-polymerizable monomer in the copolymer held
on the surface of the membrane is at least one compound selected
from the group consisting of vinyl pyrrolidone, styrene, and
(meth)acrylate derivatives.
8. The hollow fiber membrane according to claim 7, wherein the
(meth)acrylate derivative is a compound selected from the
components of the following formulas (1), (2), and (3), 4wherein
R.sup.1 is a hydrogen atom or a methyl group and R.sup.2 is a
hydrogen atom or an aliphatic or aromatic hydrocarbon group having
1-20 carbon atoms. 5wherein R.sup.3 is a hydrogen atom or a methyl
group, R.sup.4 is a hydrogen atom or an aliphatic or aromatic
hydrocarbon group having 1-20 carbon atoms, and A indicates O or
OR.sup.5O, wherein R.sup.5 is a substituted or unsubstituted
alkylene group having 1-10 carbon atoms, 6wherein R.sup.6 is a
hydrogen atom or a methyl group, R.sup.8 is a hydrogen atom or an
aliphatic or aromatic hydrocarbon group having 1-20 carbon atoms,
and R.sup.7 is a substituted or unsubstituted alkylene group having
1-10 carbon atoms.
9. A method of preparing a hollow fiber membrane comprising
simultaneously discharging a hollow space inner solution from the
inner side of double spinning nozzles and a synthetic polymer
solution from the outer side of the double spinning nozzles and
immersing the spun yarns into a coagulation bath located below the
spinning nozzles, wherein a solution prepared by dissolving
0.001-10 wt % of a copolymer of 2-methacryloyloxyethyl
phosphorylcholine and other vinyl-polymerizable monomers is used as
the hollow space inner solution or as a coagulation bath
solution.
10. A method of preparing a hollow fiber membrane comprising
passing a solution of 0.001-10 wt % of a copolymer of
2-methacryloyloxyethyl phosphorylcholine and other
vinyl-polymerizable monomers through a hollow space of hollow fiber
membrane made from a synthetic polymer and/or the outer side of the
hollow fiber membrane, thereby causing the copolymer to be adsorbed
onto the surface of the hollow fiber membrane.
Description
TECHNICAL FIELD
[0001] The present invention relates to a hollow-fiber membrane
with a modified membrane surface. More particularly, the present
invention relates to a hollow fiber membrane of which the surface
has been modified to control adsorption of proteins onto the
surface or to suppress interaction of blood components on the
surface, and to a method for preparing the hollow-fiber membrane.
The hollow fiber membrane of the present invention can be used as a
membrane for medical treatment suitable for purification of blood
such as hemodialysis and blood filtration or as a permselective
membrane used in the pharmaceutical industry or the food
industry.
BACKGROUND ART
[0002] Hollow fiber membranes made from various materials are
widely used as permselective membranes for medical applications
such as hemodialysis and blood filtration, as well as for the
pharmaceutical industry, food industry, and the like. The hollow
fiber membranes used in such applications must have superior
mechanical strength and chemical stability, possess easily
controllable permeability, release a minimal amount of materials,
exhibit almost no interaction with biological components, and be
safe for living bodies. However, there have been no hollow fiber
membranes completely satisfying all of these requirements.
[0003] When the material is a synthetic polymer, for example, the
surface is generally hydrophobic. Unduly weak hydrophilic
properties tend to cause the material to react with blood
components, cause the blood to easily coagulate, and impair the
permeability performance of the hollow fiber membrane due to
adsorption of protein components. A study for providing the hollow
fiber membrane made from such a synthetic polymer with
compatibility with blood by incorporating a polymer with
hydrophilic properties has been undertaken. For instance, a
permselective membrane made from a polysulfone-based polymer with a
hydrophilic polymer incorporated therein and a method of
manufacturing such a membrane have been proposed. Such a membrane,
however, exhibits only poor wetting properties and tends to
coagulate blood due to decreased compatibility with blood, if the
content of the hydrophilic polymer is small. On the other hand, if
the content of the hydrophilic polymer is large, the amount of the
hydrophilic polymer dissolved from the membrane increases, although
the blood coagulation can be suppressed.
[0004] Japanese Patent Applications Laid-open No. S61-238306 and
No. S63-97666 disclose a method for preparing a polysulfone-based
separation membrane in which a membrane-forming raw material
solution contains a polysulfone-based polymer, a hydrophilic
polymer, and an additive acting as a non-solvent or a swelling
agent on the polysulfone-based polymer. These patents, however, do
not describe a method for reducing dissolution of hydrophilic
polymers. Japanese Patent Applications Laid-open No. S63-97205,
S63-97634, and H04-300636 disclose a method of reducing dissolution
of hydrophilic polymers from the polysulfone-based separation
membrane prepared by the above method by insolubilizing the
hydrophilic polymers by means of a radiation treatment and/or a
heat treatment of the membrane. However, this method impair
compatibility of the membrane with blood, possibly due to the
insolubility of the hydrophilic polymer caused by cross-linking.
The membrane obtained by this method contains the hydrophilic
polymer in thick membrane areas (inner parts of membrane) as well,
precluding the thick membrane areas from exhibiting required
hydrophobicity.
[0005] Japanese Patent Applications Laid-open No. S61-402 and
S62-38205 disclose membranes containing a hydrophilic polymer only
in the dense layer side. Japanese Patent Application Laid-open No.
H04-300636 discloses a membrane containing polyvinyl pyrrolidone
present in a higher concentration in the inner surface side than in
other parts of the hollow fiber membrane. There patents, however,
only describe that the hydrophilic polymers are present near the
surface of the membrane coming into contact with blood, but do not
describe any specific properties of the polymers. In addition, no
sufficient hydrophobicity can be obtained in the thick membrane
areas of these hollow fiber membranes.
[0006] Several researches are being undertaken with an objective of
providing hollow fiber membranes with superior biological
compatibility by modifying the polymers so that the surface has not
only hydrophilic properties but also a structure similar to a
biomembrane. Specifically, one such research contemplates
improvement of biocompatibility of hollow fiber membranes by
incorporating a copolymer of 2-methacryloyloxyethyl
phosphorylcholine and other monomers having a structure similar to
phospholipids, major components forming biomembranes, into
synthetic polymer hollow fiber membranes.
[0007] Japanese Patent Application Laid-open No. H10-296063
discloses a polysulfone-based porous membrane and a method of
manufacturing the same. The porous membrane is produced using a
mixed solution of a copolymer of 2-methacryloyloxyethyl
phosphorylcholine and other monomers and a polysulfone as a
membrane-forming raw material solution. The membrane obtained by
this method, however, contains the copolymer of
2-methacryloyloxyethyl phosphorylcholine and other monomers in
thick membrane areas (inner parts of membrane) as well, precluding
the thick membrane areas from exhibiting hydrophobicity. In
addition, the copolymer may be dissolved or desorbed from the
membrane. Incompatibility of the copolymer and the polysulfone
resin is another problem which limits the composition of the
solvent used for preparing the mixed solution.
[0008] Japanese Patent Application Laid-open No. H05-177119
discloses a membrane produced by coating the surface of a porous
membrane made from polyolefin or polyolefin fluoride with a
copolymer of 2-methacryloyloxyethyl phosphorylcholine and
methacrylate. However, a large amount of the copolymer, for
example, an amount equivalent to 30% or more, preferably 50% or
more, of the pore surface of the porous membrane possessing 20 vol
% or more void ratio, must be covered to obtain a sufficient
effect. This causes the copolymer of 2-methacryloyloxyethyl
phosphorylcholine and methacrylate to be also coated over the pore
surface inside the hollow fiber membrane, precluding the thick
membrane areas from exhibiting hydrophobicity. In addition, the
copolymer may be dissolved or desorbed from the membrane.
[0009] More recently, diversified and sophisticated functions have
been demanded of membranes. In the field of artificial dialysis,
for example, countercurrent invasion of endotoxin from the dialysis
fluid side caused by high performance membranes has been pointed
out. To overcome this problem, development of a high performance
membrane capable of eliminating endotoxin and exhibiting no
interaction with blood components is desired.
DISCLOSURE OF THE INVENTION
[0010] An object of the present invention is to provide a hollow
fiber membrane with a surface structure similar to the structure of
biomembranes, with a surface exhibiting only small interaction with
biological components, not adsorbing proteins, being free from
deterioration in performance, and excelling in
biocompatibility.
[0011] Another object of the present invention is to provide a
hollow fiber membrane which can adsorb and trap foreign matters
such as endotoxin countercurrently flowing from outside the hollow
fiber in the thick membrane areas.
[0012] The inventors of the present invention have conducted
extensive studies to achieve the above objects. As a result, the
inventors have found that one of these objects can be achieved if a
copolymer of 2-methacryloyloxyethyl phosphorylcholine (hereinafter
referred to as "MPC") and other vinyl-polymerizable monomers (the
copolymer is hereinafter referred to as "MPC copolymer") is held on
the surface of the hollow fiber membrane so that the MPC copolymer
is present in a larger concentration than in the other parts of the
membrane. This finding has led to the completion of the present
invention.
[0013] Specifically, the present invention provides a modified
hollow fiber membrane made from a synthetic polymer selected from
the group consisting of polysulfone-based polymers,
polycarbonate-based polymers, polyamide-based polymers, polyvinyl
chloride-based polymers, polyvinyl alcohol-based polymers,
polyallylate-based polymers, polyacrylonitrile-based polymers,
polyether-based polymers, polyester-based polymers,
polyurethane-based polymers, polyacrylate-based polymers,
polyolefin-based polymers, and fluorinated polyolefin-based
polymers, and mixtures of these polymers, the hollow fiber membrane
being modified with a copolymer of MPC and other
vinyl-polymerizable monomers which is present on inside and/or
outside surface of the hollow fiber membrane in a larger
concentration than in the other parts of the membrane.
[0014] The inventors have further found that the above other object
can be achieved by forming the thick membrane areas of the hollow
fiber membrane from a synthetic polymer having a contact angle in
the range of 50.degree. to 100.degree..
[0015] The present invention further provides a method of preparing
a modified hollow fiber membrane comprising, in a dry and wet
spinning method comprising simultaneously discharging a hollow
space inner solution from the inner side of double spinning nozzles
and a synthetic polymer solution from the outer side of the double
spinning nozzles and immersing the spun yarns in a coagulation bath
located below the spinning nozzles, characterized by using a
solution prepared by dissolving 0.001-10 wt % of an MPC copolymer
as the hollow space inner solution and/or as a coagulation bath
solution. The present invention further provides a method of
preparing a modified hollow fiber membrane comprising passing a
solution of 0.001-10 wt % of MPC copolymer through a hollow space
of hollow fiber membrane made from a synthetic polymer and/or the
outer side of the hollow fiber membrane, thereby causing the
copolymer to be adsorbed onto the surface of the hollow fiber
membrane.
[0016] The present invention will be explained in more detail in
the following description, which is not intended to be limiting of
the present invention.
[0017] Synthetic polymers used as raw materials for the hollow
fiber membrane of the present invention include polysulfone-based
polymers, polycarbonate-based polymers, polyamide-based polymers,
polyvinyl chloride-based polymers, polyvinyl alcohol-based
polymers, polyallylate-based polymers, polyacrylonitrile-based
polymers, polyether-based polymers, polyester-based polymers,
polyurethane-based polymers, polyacrylate-based polymers,
polyolefin-based polymers, and fluorinated polyolefin-based
polymers, and mixtures of these polymers. The term "-based
polymers" used in the present invention indicates that the polymers
include not only homopolymers but also copolymers. Any monomers can
be used as the components for the copolymers inasmuch as the
resulting copolymers retain the characteristics of their base
polymer.
[0018] Specific examples of the polymers include polysulfone,
polyether sulfone, polyarylether sulfone, polyallylate-polyether
sulfone-polymer alloy, polycarbonate, polyvinyl chloride, vinyl
chloride-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer,
polyethylene terephthalate, polybuthylene terephthalate, polyamide
6, polyamide 66, polyacrylonitrile, poly(methyl acrylate),
poly(butyl acrylate), polyethylene, polypropylene,
poly-4-methylpentene-1, polyvinylidene fluoride, and the like.
[0019] In addition, a synthetic polymer having a contact angle in
the range of 50.degree. to 100.degree. is used as a material for
forming the thick membrane areas of the hollow fiber membrane to
achieve the object of the present invention. The contact angle as
used in the present invention is a contact angle with water and can
be determined by forming a flat plate from the synthetic polymer
used for the thick membrane areas, placing a water drop on the
surface, and measuring the angle made by the synthetic polymer and
the water surface. The lower the water contact angle, the higher
the hydrophilic properties; and the higher the water contact angle,
the higher the hydrophobic properties. When the synthetic polymer
forming the thick membrane areas is a polymer mixture, at least the
major polymer component forming the thick membrane areas must have
a contact angle between 50.degree. and 100.degree..
[0020] Endotoxin which is a pollutant in dialysis fluids has a
lipid A site, a structure derived from a fatty acid, and tends to
be adsorbed on the surface of hydrophobic polymers due to the
hydrophobic properties of this site. Since foreign matters such as
endotoxin contained in the dialysis fluid on the outside surface
side of hollow fiber membrane can be efficiently adsorbed by
forming the thick membrane areas from a synthetic polymer having a
contact angle of 50.degree. to 100.degree., pollution of blood due
to reverse permeation of endotoxin to the inside surface side can
be prevented. If the contact angle is greater than 100.degree., the
adsorptive activity of blood proteins tends to change. Therefore,
the major raw material for the membrane forming the thick membrane
areas preferably has a contact angle between 50.degree. and
100.degree..
[0021] Any synthetic polymers having a contact angle of this range
and capable of forming a hollow fiber membrane can be used as raw
materials in the present invention. Examples include
polysulfone-based polymers, polycarbonate-based polymers, polyvinyl
chloride-based polymers, polyallylate-based polymers,
polyether-based polymers, polyester-based polymers,
polyurethane-based polymers, polyacrylate-based polymers,
polyolefin-based polymers, and fluorinated polyolefin-based
polymers, and mixtures of these polymers. The term "-basedpolymers"
used here indicates that the polymers include not only homopolymers
but also copolymers. Any monomers can be used as the components for
the copolymers inasmuch as the resulting copolymers retain the
characteristics of their base polymer.
[0022] Specific examples of the polymers include polysulfone,
polyether sulfone, polyarylether sulfone, polyallylate-polyether
sulfone-polymer alloy, polycarbonate, polyvinyl chloride, vinyl
chloride-vinyl acetate copolymer, polyethylene terephthalate,
polybuthylene terephthalate, poly(methyl acrylate), poly(butyl
acrylate), polyethylene, polypropylene, poly-4-methylpentene-1,
polyvinylidene fluoride, and the like.
[0023] As the other vinyl-polymerizable monomer for forming
copolymers with MPC, one or more vinyl-polymerizable monomers
selected from the group consisting of vinyl pyrrolidone, styrene,
and (meth)acrylate derivatives can be used. The (meth)acrylate
derivatives preferably used as vinyl-polymerizable monomers include
the compounds of the following formulas (1), (2), or (3), 1
[0024] wherein R.sup.1 is a hydrogen atom or a methyl group and
R.sup.2 is a hydrogen atom or an aliphatic or aromatic hydrocarbon
group having 1-20 carbon atoms. 2
[0025] wherein R.sup.3 is a hydrogen atom or a methyl group,
R.sup.4 is a hydrogen atom or an aliphatic or aromatic hydrocarbon
group having 1-20 carbon atoms, and A indicates O or OR.sup.5O,
wherein R.sup.5 is a substituted or unsubstituted alkylene group
having 1-10 carbon atoms, 3
[0026] wherein R.sup.6 is a hydrogen atom or a methyl group,
R.sup.8 is a hydrogen atom or an aliphatic or aromatic hydrocarbon
group having 1-20 carbon atoms, and R.sup.7 is a substituted or
unsubstituted alkylene group having 1-10 carbon atoms.
[0027] Suitable monomers are selected according to the
characteristics desired for the copolymer.
[0028] As specific compounds, butyl methacrylate, benzyl
methacrylate, methacryloyloxyethyl phenylcarbamate, phenyl
methacryloyloxyethyl carbamate, and the like can be given.
[0029] If the monomer unit content of MPC in the copolymer, which
is the ratio of MPC (A mols) to the total of MPC (A mols) and other
vinyl-polymerizable monomer components (B mols), A/(A+B), is small,
the copolymer tends to exhibit insufficient biocompatibility and
hydrophilic properties. If the MPC monomer unit content is large,
on the other hand, the copolymer exhibits increased solubility in
water and decreased solubility in organic solvents, resulting in an
increase in the amount of membrane materials dissolved in water or
other problems such as limited application of the hollow fiber
membrane. For this reason, the monomer unit content of MPC in the
present invention is preferably from 0.05 to 0.95, and more
preferably from 0.1 to 0.5.
[0030] Although the biocompatibility on the surface of the hollow
fiber membrane of the present invention is affected by the type of
vinyl-polymerizable monomers copolymerized with MPC and the MPC
monomer unit content, the biocompatibility is basically determined
by the amount of MPC present on the membrane surface. Such an
amount of MPC monomer units can be determined by analyzing the
surface of hollow fiber membrane by X-ray photoelectron
spectroscopy. Since the ratio of elements present near the surface
can be determined by the X-ray photoelectron spectroscopy, the MPC
monomer unit concentration (the weight of MPC monomer unit/the
weight of membrane) near the surface can be calculated from the
chemical formula of the MPC copolymer and the chemical formula of
polymer forming the membrane. Since this is the concentration near
the surface of the membrane, the value is employed as the MPC
monomer unit concentration on the membrane surface. The MPC monomer
unit concentration on the membrane surface determined in this
manner is preferably 5 wt % or more, and more preferably 8 wt % or
more for the hollow fiber membrane to exhibit biocompatibility. To
increase the MPC monomer unit concentration on the membrane
surface, not only the concentration of MPC monomer unit in the
copolymer but also the concentration of MPC copolymer per unit
weight of membrane must be increased. This leads to an increase in
the amount of dissolved materials. Therefore, the MPC monomer unit
content is preferably 50 wt % or less, and more preferably 40 wt %
or less.
[0031] The MPC copolymer may be present in a concentration higher
than the other part of the membrane either on the inside surface or
the outside surface, or on both surfaces of the hollow fiber
membrane. The surface on which the MPC copolymer is present in a
higher concentration than in other parts of the hollow fiber
membrane is suitably selected according to the application or the
manner of use of the hollow fiber membrane.
[0032] In the hollow fiber membrane described in Japanese Patent
Application Laid-open No. H05-177119, MPC copolymer not only covers
porous surface of the porous hollow fiber membrane, but also is
present on the porous surface of inner parts of membrane (thick
membrane areas). On the other hand, in the present invention the
amount of MPC copolymer present in pores in the inner parts of
membrane (thick membrane areas) should be as small as possible, but
the MPC copolymer should be unevenly distributed only on the
surface of the hollow fiber membrane.
[0033] The MPC copolymer can be unevenly distributed on the surface
of the membrane by adjusting the molecular weight of the MPC
copolymer held on the surface or by adjusting the membrane
structure such as a void ratio, pore diameter, and the like of the
hollow fiber membrane.
[0034] Because the MPC copolymer is unevenly distributed on the
surface of the membrane in the present invention, the concentration
of the MPC monomer unit on the surface of the hollow fiber membrane
can be maintained sufficiently high, notwithstanding a very small
concentration of the MPC copolymer per unit weight of the membrane
(bulk concentration) The bulk concentration may be in the range of
0.001-1.0 wt %, preferably 0.05-0.5 wt %. The bulk concentration of
MPC copolymer can be determined by preparing a sufficiently washed
and dried sample of hollow fiber membrane and analyzing fragments
derived from MPC in this sample by pyrolysis gas
chromatography.
[0035] The MPC copolymer is used as a solution in manufacturing the
hollow fiber membrane of the present invention. The MPC copolymer
may have as high molecular weight as possible as long as the
polymer is dissolved in the solvent without problem. If the
molecular weight is too small, the MPC copolymer tends to liquate
out or be released from the membrane. In manufacturing the hollow
fiber membrane of the present invention, the solution of MPC
copolymer is caused to come into contact with the material of the
membrane from the inside and/or outside surfaces of the hollow
fiber membrane. If the molecular weight of the MPC copolymer is too
small, the MPC copolymer is diffused in the membrane so that the
MPC copolymer is incorporated all over the membrane. Thus, the MPC
copolymer with such a small molecular weight cannot achieve the
feature of the present invention that the hydrophilic property
polymer is unevenly distributed over the inside and/or outside
surfaces of the membrane. For these reasons, the MPC copolymer has
a molecular weight preferably 5,000 or more, and more preferably
10,000 or more.
[0036] In manufacturing the hollow fiber membrane of the present
invention, the solution of MPC copolymer may be caused to come into
contact with the material of the membrane from the inside and/or
outside surfaces of the hollow fiber membrane, thereby causing the
MPC copolymer to be held on the inside and/or outside surfaces. The
resulting hollow fiber membrane has a structure with a dense layer
on the membrane surface on which the MPC copolymer is held. If the
MPC copolymer molecule is large enough to preclude dispersion of
the copolymer into the pores in membrane, the amount of the MPC
copolymer incorporated into the inner parts of membrane (thick
membrane areas) can be minimized. Form this point of view, it is
preferable that the hollow fiber membrane of the present invention
have a structure with a dense layer on the membrane surface on
which the MPC copolymer is held.
[0037] The hollow fiber membrane of the present invention having
thick membrane areas made from a synthetic polymer having a contact
angle in the range of 50.degree. to 100.degree. can adsorb and trap
foreign matters such as endotoxin countercurrently flowing from
outside the hollow fiber. For this reason, the thick membrane areas
preferably have a porous structure with developed networks rather
than a finger void structure having independent large voids. To
obtain hollow fiber membrane with such a structure, additives such
as tetraethylene glycol, polyvinyl pyrrolidone, and the like can be
added to the raw material solution for forming the membrane.
[0038] As described above, the hollow fiber membrane can be
modified in the present invention by unevenly distributing the MPC
copolymer on the membrane surface. Such a hollow fiber membrane can
be obtained by a method of causing the MPC copolymer adsorbed on
the surface of a previously manufactured hollow fiber membrane, as
mentioned above, or by a method of unevenly distributing the MPC
copolymer on the membrane surface when the membrane is
manufactured.
[0039] A conventionally known dry and wet spinning method can be
used for unevenly distributing the MPC copolymer on the membrane
surface when the membrane is manufactured. Specifically, a raw
material fluid for the preparation of membrane and an hollow space
inner fluid are simultaneously discharged from tube-in-orifice type
double spinning nozzles, spun yarns are caused to run in air, and
immersed in a coagulation bath containing water as a major
coagulation medium installed under the spinning nozzles. The
coagulated yarns are wound around a reel. The wound hollow fiber
membrane is washed to remove excessive additives and solvents.
Glycerin is added as required, followed by drying by dry heating
and the like to obtain a hollow fiber membrane. To unevenly
distribute the MPC copolymer on the inner surface during the
manufacture of membrane, an MPC copolymer solution is used as a
hollow space inner solution. To unevenly distribute the MPC
copolymer on the outer surface, on the other hand, the MPC
copolymer solution is used as a coagulating solution.
[0040] The hollow fiber membrane obtained by these methods release
only a very small amount of eluted materials. This is thought to be
the result of the following mechanism of membrane structure
formation. Specifically, the membrane-forming raw material solution
and hollow space inner solution in which the MPC polymer is
dissolved are brought to come into contact at the moment when these
solutions are discharged from spinning nozzles. This causes the
membrane-forming raw material solution to coagulate, while the MPC
polymer is entangled with molecular chains of the synthetic polymer
forming the hollow-fiber membrane or incorporated into dense
structures near the inner surface, thereby firmly immobilizing the
MPC polymer. Absence of extra MPC polymer inside the membrane is
also thought to contribute to the very small amount of eluted
materials.
[0041] This method can be applied to any synthetic polymer which
can be prepared into membranes by the dry wet spinning method. A
polymer solution in which a synthetic polymer used as a
membrane-forming material and additives are uniformly dissolved in
a solvent is used as the membrane-forming raw material solution. A
non-solvent for the synthetic polymer or a mixture of such as a
non-solvent and a solvent can be used as a hollow space inner
solution which forms hollow areas. The performance of the obtained
hollow-fiber membrane is generally controlled by the ratio of the
non-solvent and the solvent in the hollow space inner solution.
Such a ratio is determined according to the object of
application.
[0042] As an MPC copolymer, a copolymer soluble in the hollow space
inner solution and/or coagulating bath solution can be selected and
used.
[0043] The concentration of the MPC copolymer in the hollow space
inner solution and/or coagulating bath solution in the range of
0.001-10 wt % is sufficient for attaching the MPC copolymer to the
membrane surface necessary for the hollow-fiber membrane to exhibit
biocompatibility, with the range of 0.01-5 wt % being more
preferable.
[0044] Various known methods of manufacturing hollow-fiber
membranes can be used for previously preparing the hollow-fiber
membrane to be modified. Any synthetic polymers to which these
membrane-forming methods are applicable can be used as the material
for forming the hollow-fiber membrane. In this method, a solution
for adsorption treatment prepared by dissolving the MPC copolymer
in a suitable solvent is caused to come into contact with the
membrane surface on which the MPC copolymer should be unevenly
distributed, thereby causing the MPC copolymer to be adsorbed. The
MPC copolymer can be adsorbed using any appropriate method such as
a method of immersing the hollow fiber into the adsorbed solution,
a method of passing the adsorbed solution through the hollow space
or outside the hollow-fiber membrane, or a method of encapsulating
the adsorbed solution into the hollow space or outside the
hollow-fiber membrane. After that, excess copolymer and solvent are
removed by washing. Then, the product is dried, if necessary. These
processing can be carried out either in the module step when the
hollow fiver has been formed or in the step before formation of the
hollow fiber. The concentration of the MPC copolymer in the
adsorbed solution in the range of 0.001-10 wt % is sufficient for
attaching the MPC copolymer to the membrane surface necessary for
the hollow-fiber membrane to exhibit biocompatibility, with the
range of 0.01-5 wt % being more preferable.
BEST MODE FOR CARRYING OUT THE INVENTION
[0045] The present invention will now be described in more detail
by way of working examples and test examples, which should not be
construed as limiting the present invention.
[0046] (Measurement of Amount of Eluted Materials)
[0047] 1.5 g of hollow fiber membrane was put into 150 ml of
distilled water and heated at 70.degree. C. for one hour to obtain
an extract. UV radiation absorbance of the extract at a wavelength
of 220-350 nm was measured using distilled water heated at
70.degree. C. for one hour without adding the hollow fiber membrane
as a control. The amount of eluted materials is indicated by the
highest value of absorbance in the wavelength range of 220-350
nm.
EXAMPLE 1
[0048] 18 parts of polysulfone ("Ultrason S3010" manufactured by
BASF) was added to a mixture of 57 parts of N,N-dimethylacetamide
(DMAC) and 25 parts of tetraethylene glycol (TEG). The mixture was
stirred for 6 hours at 60.degree. C. and dissolved to obtain a
membrane-forming raw material solution. The raw material solution
maintained at a temperature of 45.degree. C. was discharged from
spinnerets with an annular orifice together with a 40% aqueous
solution of DMAC, to which 1% of a copolymer of MPC and
methacryloyloxyethyl phenyl carbamate (MPC monomer unit
content=0.31, molecular weight=109,000) was added as an internal
coagulate solution. The spun raw material was passed through a
water bath, placed 36 cm lower than the discharge nozzle, at
55.degree. C. to be wound around a reel, and washed with hot water
at 90.degree. C. to remove any excess copolymer and the solvent.
The resulting hollow fiber membrane was confirmed to have a water
permeability of 325 ml/m.sup.2.multidot.mmHg.multidot.hr, an MPC
copolymer concentration on the inner side surface of 13 wt %, and a
bulk concentration of 0.25 wt %. The absorbance of the extract
obtained from the hollow fiber membrane determined by the elusion
material measurement method was 0.020.
EXAMPLE 2
[0049] A hollow fiber membrane was prepared in the same manner as
in Example 1, except for using a 40% aqueous solution of DMAC, to
which 1% of a copolymer of MPC and butyl methacryate (MPC monomer
unit content=0.40, molecular weight=122,000) was added as an
internal coagulate solution. The resulting hollow fiber membrane
was confirmed to have a water permeability of 299
ml/m.sup.2.multidot.mmHg.multidot.hr, an MPC copolymer
concentration on the inner side surface of 18 wt %, and a bulk
concentration of 0.2 wt %. The absorbance of the extract obtained
from the hollow fiber membrane determined by the elusion material
measurement method was 0.025.
EXAMPLE 3
[0050] A hollow fiber membrane was prepared in the same manner as
in Example 1, except for using a 40% aqueous solution of DMAC, to
which 1% of a copolymer of MPC and phenyl methacryloyloxyethyl
carbamate (MPC monomer unit content=0.28, molecular weight=160,000)
was added as an internal coagulate solution. The resulting hollow
fiber membrane was confirmed to have a water permeability of 280
ml/m.sup.2.multidot.mmHg.mu- ltidot.hr, an MPC copolymer
concentration on the inner side surface of 15 wt %, and a bulk
concentration of 0.3 wt %. The absorbance of the extract obtained
from the hollow fiber membrane determined by the elusion material
measurement method was 0.018.
EXAMPLE 4
[0051] A hollow fiber membrane was prepared in the same manner as
in Example 1, except for using a 40% aqueous solution of DMAC, to
which 1% of a copolymer of MPC and benzyl methacryate (MPC monomer
unit content=0.29, molecular weight=132,000) was added as an
internal coagulate solution. The resulting hollow fiber membrane
was confirmed to have a water permeability of 310
ml/m.sup.2.multidot.mmHg.multidot.hr, an MPC copolymer
concentration on the inner side surface of 14 wt %, and a bulk
concentration of 0.25 wt %. The absorbance of the extract obtained
from the hollow fiber membrane determined by the elusion material
measurement method was 0.019.
EXAMPLE 5
[0052] A hollow fiber membrane was prepared in the same manner as
in Example 1, except for using a 40% aqueous solution of DMAC as an
internal coagulate solution. The resulting hollow fiber membrane
was dipped into a 40% aqueous solution of ethanol, to which 1% of a
copolymer of MPC and phenyl methacryloyloxyethyl carbamate (MPC
monomer unit content=0.31, molecular weight=109,000) was added, to
adsorb the MPC copolymer. Then, the hollow fiber membrane was
washed with hot water at 90.degree. C. to remove any excess
copolymer and ethanol. The resulting hollow fiber membrane was
confirmed to have a water permeability of 330
ml/m.sup.2.multidot.mmHg.multidot.hr, an MPC copolymer
concentration on the inner side surface of 12 wt %, and a bulk
concentration of 0.4 wt %. The absorbance of the extract obtained
from the hollow fiber membrane determined by the elusion material
measurement method was 0.015.
EXAMPLE 6
[0053] 18 parts of polysulfone ("Ultrason S3010" manufactured by
BASF) and 3 parts of polyvinyl pyrrolidone ("Plasdone K90"
manufactured by ISP) were added to 79 parts of DMAC. The mixture
was stirred for 6 hours at 60.degree. C. and dissolved to obtain a
membrane-forming raw material solution. The raw material solution
maintained at a temperature of 45.degree. C. was discharged from
spinnerets with an annular orifice together with a 40% aqueous
solution of DMAC, to which 1% of a copolymer of MPC and
methacryloyloxyethyl phenyl carbamate (MPC monomer unit
content=0.31, molecular weight=109,000) was added as an internal
coagulate solution. The spun raw material was passed through a
water bath, placed 36 cm lower than the discharge nozzle, at
55.degree. C. to be wound around a reel, and washed with hot water
at 90.degree. C. to remove any excess copolymer and the solvent.
The resulting hollow fiber membrane was confirmed to have a water
permeability of 142 ml/m.sup.2.multidot.mmHg.multidot.hr, an MPC
copolymer concentration on the inner side surface of 17 wt %, and a
bulk concentration of 0.1 wt %. The absorbance of the extract
obtained from the hollow fiber membrane was 0.022.
EXAMPLE 7
[0054] A polyacrylonitrile-based synthetic polymer made from 92
parts of polyacrylonitrile, 6 parts of methyl acrylate, 1.5 parts
of acrylic acid, and 0.5 part of methallylsulfonic acid was added
to 79 parts of DMAC. The mixture was stirred for 6 hours at
60.degree. C. and dissolved to obtain a membrane-forming raw
material solution. The raw material solution maintained at a
temperature of 45.degree. C. was discharged from spinnerets with an
annular orifice together with a 40% aqueous solution of DMAC, to
which 1% of a copolymer of MPC and methacryloyloxyethyl phenyl
carbamate (MPC monomer unit content=0.31, molecular weight=109,000)
was added as an internal coagulate solution. The spun raw material
was passed through a water bath, placed 36 cm lower than the
discharge nozzle, at 55.degree. C. to be wound around a reel, and
washed with hot water at 90.degree. C. to remove any excess
copolymer and the solvent. The resulting hollow fiber membrane was
confirmed to have a water permeability of 162
ml/m.sup.2.multidot.mmHg.multidot.hr, an MPC copolymer
concentration on the inner side surface of 20 wt %, and a bulk
concentration of 0.2 wt %. The absorbance of the extract obtained
from the hollow fiber membrane determined by the elusion material
measurement method, was 0.022.
EXAMPLE 8
[0055] High density polyethylene was melt-spun using spinnerets
having an annular orifice at 165.degree. C. The resulting non-drawn
yarns were annealed on a roller heated at 115.degree. C. and drawn
at 25.degree. C. (cold drawing) by 30% and at 80.degree. C. (hot
drawing) by 200%. The resulting hollow fiber membrane has a pore
diameter of 0.01 .mu.m. The resulting hollow fiber membrane was
dipped into a 40% aqueous solution of ethanol, to which 1% of a
copolymer of MPC and phenyl methacryloyloxyethyl carbamate (MPC
monomer unit content=0.31, molecular weight=109,000) was added, to
adsorb the MPC copolymer. Then, the hollow fiber membrane was
washed with hot water at 90.degree. C. to remove an excess amount
of the MPC copolymer and ethanol. The resulting hollow fiber
membrane was confirmed to have a water permeability of 562
ml/m.sup.2.multidot.mmHg.multidot.hr, an MPC copolymer
concentration on the inner side surface of 13 wt %, and a bulk
concentration of 0.2 wt %. The absorbance of the extract obtained
from the hollow fiber membrane was 0.022.
COMPARATIVE EXAMPLE 1
[0056] A hollow fiber membrane was prepared in the same manner as
in Example 1, except for using a 40% aqueous solution of DMAC as an
internal coagulate solution. The resulting hollow fiber membrane
was confirmed to have a water permeability of 957
ml/m.sup.2.multidot.mmHg.multidot.hr, an MPC copolymer
concentration on the inner side surface of 0 wt %, and a bulk
concentration of 0 wt %.
COMPARATIVE EXAMPLE 2
[0057] Next, as a Comparative Example a hollow fiber membrane was
prepared according to the conventional method described in Japanese
Patent Application Laid-open No. H05-177119.
[0058] High density polyethylene was melt-spun using spinnerets
having an annular orifice at 165.degree. C. The resulting non-drawn
yarns were annealed on a roller heated at 115.degree. C. and drawn
at 25.degree. C. (cold drawing) by 50% and at 110.degree. C. (hot
drawing) by 300%. The resulting hollow fiber membrane has a pore
diameter of 0.3 .mu.m. The resulting hollow fiber membrane was
dipped into a 40% aqueous solution of ethanol, to which 1% of a
copolymer of MPC and phenyl methacryloyloxyethyl carbamate (MPC
monomer unit content=0.31, molecular weight=109,000) was added, to
adsorb the MPC copolymer. Then, the hollow fiber membrane was
washed with hot water at 90.degree. C. to remove an excess amount
of the MPC copolymer and ethanol. The resulting hollow fiber
membrane was confirmed to have a water permeability of 1,620
m/m.sup.2.multidot.mmHg.multidot.hr, an MPC copolymer concentration
on the inner side surface of 18 wt %, and a bulk concentration of
2.5 wt %. The extract obtained from the hollow fiber membrane
exhibited a high absorbance of 0.102.
TEST EXAMPLE 1
[0059] The ultra filtration rate (UFR) of bovine blood plasma was
measured using the hollow fiber membrane obtained in Examples 1-8
and Comparative Example 1. Specifically, a miniature module was
prepared by bundling 140 sheets of hollow fiber membrane with a
length of 15 cm. Bovine blood plasma to which heparin was added
(heparin 5000 IU/l, protein concentration: 6.5 g/dl) was heated to
37.degree. C. and passed through the miniature module at a linear
velocity of 0.4 cm/sec at a membrane pressure difference of 25 mmHg
for 120 minutes to ultra filter the blood plasma. The filtrate was
sampled at 15, 30, 60, and 120 minutes. The weight of the samples
was measured to calculate the UFR. The results are shown in Table
1, which indicates that no performance deterioration of UFR was
seen in the hollow fiber membranes with MPC copolymer unevenly
distributed in the inner surface.
1 TABLE 1 Hollow fiber UFR (ml/m.sup.2 .multidot. mmHg .multidot.
hr) membrane 15 min 30 min 60 min 120 min Example 1 41 42 41 42
Example 2 39 39 38 39 Example 3 37 38 38 38 Example 4 42 42 41 42
Example 5 43 44 43 43 Example 6 36 35 37 35 Example 7 28 29 28 29
Example 8 46 45 48 45 Comparative 30 28 23 18 Example 1
TEST EXAMPLE 2
[0060] The permeability of endotoxin was measured using the hollow
fiber membranes obtained in Examples 1-8 and Comparative Example 2.
Specifically, a test solution with an endotoxin concentration of
100 ng/ml was caused to permeate through a module with a membrane
area of 120 cm.sup.2 from the dialysis fluid side to the blood side
for 10 minutes at a rate of 5 ml/min. The filtrate was collected at
the blood side outlet to detect endotoxin using an endotoxin
detecting LAL reagent (a helmet crab corpuscle extract "HS-J"
manufactured by Wako Pure Chemical Industries, Ltd.). As a result,
no endotoxin was detected in the filtrates of the hollow fiber
membranes obtained in Examples 1-8, whereas 12 ng/ml of endotoxin
was detected in the filtrate of the hollow fiber membrane obtained
in Comparative Example 2.
TEST EXAMPLE 3
[0061] The thrombocytes adhesion to the hollow fiber membranes
obtained in Examples 1-8 and Comparative Example 1 was evaluated.
Specifically, a miniature module was prepared by bundling 28 sheets
of hollow fiber membrane with a length of 14 cm. 7 cc of fresh
human blood to which heparin was added was passed through the
module in 5 minutes, following which 10 cc of a physiological
saline solution was caused to flow to remove blood. Next, the
hollow fiber membrane was cut into short pieces of 2 to 3 mm in
length, which were put into a physiological saline solution
containing 0.5% Triton X-100 (polyoxyethylene (10) octylphenyl
ether). The mixture was irradiated with supersonic waves. Isolated
lactic acid dehydrogenase (LDH) was quantitatively determined.
Since the LDH is an enzyme present in cell membranes and almost all
cells adhering to the membrane surface have been confirmed to be
thrombocytes by electron microscope observation, the determined LDH
value was used for relative evaluation of thrombocytes adhered to
the membrane surface. The results are shown in Table 2, which
indicates that only a small amount of thrombocytes have adhered to
the surface of the hollow fiber membranes with MPC copolymer
unevenly distributed in the inner surface.
2 TABLE 2 Hollow fiber LDH released from hollow fiber membrane
membrane (unit/m.sup.2) Example 1 7.7 Example 2 8.2 Example 3 5.5
Example 4 7.0 Example 5 8.0 Example 6 3.4 Example 7 2.4 Example 8
5.4 Comparative 34 Example 1
INDUSTRIAL APPLICABILITY
[0062] Because the hollow fiber membrane of the present invention
comprises a copolymer of 2-methacryloyloxyethyl phosphorylcholine
and other vinyl-polymerizable monomers unevenly distributed inside
and/or outside the surface of the membrane, the membrane surface
can be modified without increasing materials dissolved out from the
membrane. Specifically, the membrane releases or dissolves out the
least amount of materials, does not suffer from deterioration of
its performance, activates thrombocytes very slightly, produces
filtrate containing no detected endotoxin, and is useful in medical
application such as hemodialysis and blood filtration or as a
permselective membrane used in the pharmaceutical industry and the
food industry.
* * * * *